The paradox of the novel 1 L polyethylene glycol bowel preparation: efficacy, not tolerability, is the great new!

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Abstract
Improving patient perception of colonoscopy plays a key role in increasing adherence to screening programs, which is crucial for screening effectiveness in colorectal cancer (CRC) prevention. From the patient perspective, bowel preparation is recognized as the most burdensome aspect of the whole procedure, sometimes even worse than the examination itself, and this represents a major barrier to screening colonoscopy [1]. Thus, in recent years great attention has been paid to improving the tolerability of bowel preparation. Complaints regarding bowel preparation typically relate to the large volumes to be consumed within a short period of time and to the unpleasant taste. “But postmarketing real-life data are needed to confirm the safety profile of this new product in a wider population with a range of comorbidities.” The adoption of split-dose regimens has undoubtedly represented the most important step toward not only an increased efficacy of bowel preparation, but also an enhanced patient acceptance. Reducing the total volume of the cleansing agents, along with an attempt to improve their palatability, are also recognised as ways to improve the patient experience of colonoscopy preparation. Although many low-volume preparations are gaining popularity at the expense of large-volume lavage solutions, many endoscopists are still skeptical of their adoption in routine practice. Concerns mainly relate to efficacy, which remains the first priority, when considering the deleterious effects of inadequate preparation on the effectiveness of colonoscopy in CRC prevention. Concern over the efficacy of low-volume bowel preparations probably reflects an endoscopist’s preconception rather than the clinical evidence. Indeed, many studies have demonstrated that low-volume preparations are not inferior to 4 L polyethylene glycol (PEG) electrolyte solutions in terms of efficacy [2], and high-quality randomized controlled trials have demonstrated that, when administered in a split regimen, they guarantee levels of efficacy over the recommended standards in the screening setting [3] [4]. In this issue of Endoscopy, data on the efficacy, safety, and tolerability of a novel 1 L PEG 3350-based bowel preparation (NER1006) for colonoscopy by two industry-funded Phase 3 studies are presented [5] [6]. These studies were two of three parallel randomized studies (also including the NOCT study carried out in the United States) [7] aimed at evaluating NER1006 in different dosing regimens, as part of the product label, compared with key leading different low-volume comparators (2LPEG with ascorbate in the MORA study, sodium picosulfate with magnesium citrate [SP + MC] in the DAYB study, and trisulfate in the NOCT study). The three NER1006 studies share the same design, and this simplifies the interpretation and comparisons of results, which are summarized in [Table 1]. They have several strengths, including the rigorous statistical analysis, the large sample size, and above all, the use of blinded independent central readers for primary end point assessment in order to reduce the potential for bias in the subjective evaluation of bowel cleansing efficacy. In addition, right-sided cleansing was specified as a primary end point, and the efficacy primary end points were assessed for superiority by a preplanned analysis if noninferiority was demonstrated. It must be acknowledged that this is probably the first time that studies on bowel preparation have provided such robust and high quality data from a methodological point of view, and may potentially set a new quality standard for pivotal studies of new bowel cleansing products. Does this novel 1 L PEG-based preparation represent the final solution to achieve a highly effective, safe, and tolerated bowel preparation? There is no doubt that NER1006 appears to be a very effective preparation, but split dosing (or same-day regimen as an alternative) is an essential prerequisite for its success. It matters little that in the DAYB study, where both study preparations were given in day-before dosing, NER1006 met the primary end point of noninferiority efficacy vs. SP + MC, and was even superior at per-protocol analysis. The overall colon cleansing success of 62 % reported in the DAYB study is unacceptable. Conversely, the efficacy is very high, over the standards set by professional societies, when NER1006 is administered as either a split or same-day regimen. It is noteworthy that the true efficacy could probably have been even higher in the MORA study if the “runway time” had been optimized within the “golden 5 hours” [8] in a higher proportion of patients. In terms of efficacy, the most interesting, and on some level, unexpected, finding relates to the quality cleansing of the right colon, which is usually considered the “Achilles’ heel” of low-volume bowel preparations. In the MORA study, superiority of NER1006 vs. 2LPEG was statistically demonstrated with a split regimen at the intention-to-treat analysis and with both dose regimens at per-protocol analysis. This signal of higher cleansing efficacy in the right colon was consistent across the three studies, regardless of the administration regimen, and this suggests that it is strictly related to the properties of the product. Actually, NER1006 contains a high quantity of ascorbate components (4-fold higher than in the standard 2LPEG + Asc), which are administered in the second dose only. The increased osmotic load is thus delivered in a smaller volume and this is likely to represent the major determinant for efficacy in the proximal colon. But when we deal with hyperosmotic cleansing agents (and NER1006 should definitely be considered as an osmotic laxative), safety is an important issue, especially in an open-access system. PEG-based bowel preparations are traditionally considered the gold standard for safety. They have been purposely developed to pass...

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